This invention relates to topical delivery of substances into the skin, particularly by disruption of the stratum corneum and delivery of the substance to the epidermal layer beneath.
Delivery of substances to the body through the skin has typically been invasive, involving needles and syringes to facilitate intradermal (ID), intramuscular (AIM) or subcutaneous (SC) injection. These methods are painful for the subject, require the skills of a trained practitioner and often produce bleeding. There have more recently been efforts to overcome these disadvantages by use of devices which disrupt or abrade the stratum corneum, the thin external layer of keratinized cells about 10-20 xcexcm thick which serves as the skin""s outer barrier, with delivery of the desired substance to the exposed epidermis. The substance can then diffuse through the epidermis to the dermis which contains blood vessels and lymphatics for absorption and delivery of the substance throughout the body. For topical delivery of vaccines, the epidermis itself is a particularly desirable target for drug delivery as it is rich in antigen presenting cells. In comparison, the dermis contains fewer antigen presenting cells. The stratum corneum and epidermis do not contain nerves or blood vessels, so this method has the advantage of being essentially painless and blood-free while giving access to the skin layers capable of responding to the antigen.
The prior art reports a variety of devices and methods for disrupting the stratum corneum for the purpose of delivering substances to the body. For example, breach of the stratum corneum may be achieved by puncturing as taught in U.S. Pat. No. 5,679,647 to Carson, et al. This patent teaches that narrow diameter tynes, such as those found on devices used for tuberculin skin tests and allergy tests, can be coated with polynucleotides and used for delivery of such materials into the skin. The method of using such devices involves puncturing the skin with the tynes resulting in intracutaneous injection of the coated substance. This is in contrast to the present invention, where it has been unexpectedly discovered that substances coated onto the surface of narrow diameter micro-protrusions are delivered more effectively by lateral abrasion across the skin surface rather than by puncturing. U.S. Pat. No. 5,003,987; U.S. Pat. No. 5,879,326; and U.S. Pat. No. 3,964,482 teach breaching the stratum corneum by abrasion, however, little is known about how to optimize topical application methods to achieve efficient and efficacious delivery by this route. Such optimization is of particular interest for topical nucleic acid delivery, especially topical delivery of nucleic acid-based vaccines and gene therapies. In this regard, the most commonly suggested method for topical administration is to abrade the skin prior to application of the vaccine. However, it has now been unexpectedly found that delivery of nucleic acids and peptides or polypeptides such as allergens is more efficient and more efficacious when the substance is delivered simultaneously with abrasion.
The present invention provides optimized methods for topical delivery of substances, particularly nucleic acids, amino acids, amino acid derivatives, peptides or polypeptides. It has been discovered that nucleic acids exhibit enhanced gene expression and produce an enhanced immune response to the expressed protein when they are delivered simultaneously with abrasion of the stratum corneum. Similarly, allergens delivered simultaneously with abrasion produce a more vigorous immune response than conventional allergen testing methods.